US-20260125335-A1 - SYNTHETIC CANNABINOID ANALOGS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF TREATING BACTERIAL INFECTIONS AND OTHER DISORDERS

Abstract

Cannabinoid analogs disclosed herein may exhibit antibacterial and anti-inflammatory properties. Pharmaceutical compositions comprising the cannabinoid analogs may be used to treat bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA) infections, as well as various disorders associated with chronic inflammation, such as arthritis. In some aspects, a pharmaceutical composition may be administered to an individual who has been exposed or is at risk of exposure to Bacillus anthracis or Bacillus anthracis spores.

Inventors

• Jonnie R. Williams, SR.

Assignees

• MIRALOGX LLC

Dates

Publication Date

20260507

Application Date

20240523

Claims (20)

1. 1 .- 5 . (canceled)
2. 6 . A compound having a structure of Formula (VI): wherein R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, alkyl, —O-alkyl, NR A R B , —S-alkyl, —SO-alkyl, —SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, —COH, —C(O)—C 1-4 alkyl, —C(O)O C 1-4 alkyl, —NR C R D , —S-alkyl, —SO-alkyl and —SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; or a pharmaceutically acceptable salt, ester or ether thereof.
3. 7 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 6 and a pharmaceutically acceptable vehicle therefor.
4. 8 . A method of treating a bacterial infection comprising administering to an individual in need thereof a pharmaceutical composition of claim 7 .
5. 9 . A method of treating anxiety, depression or pain comprising administering to an individual in need thereof a pharmaceutical composition of claim 7 .
6. 10 . (canceled)
7. 11 . A compound of claim 6 which has a structure selected from the group consisting of: or a pharmaceutically acceptable salt, ester or ether thereof.
8. 12 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 11 and a pharmaceutically acceptable vehicle therefor.
9. 13 . A method of treating a bacterial infection comprising administering to an individual in need thereof a pharmaceutical composition of claim 12 .
10. 14 . The method of claim 13 , wherein the bacterial infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection.
11. 15 . The method of claim 13 , wherein the pharmaceutical composition is administered to an individual who has been exposed or is at risk of exposure to Bacillus anthracis or Bacillus anthracis spores.
12. 16 .- 20 . (canceled)
13. 21 . The compound of claim 6 , wherein R 1 is CH 3 , R 3 is H, and R 4 is H or CH 3 alkyl.
14. 22 . The compound of claim 21 , wherein R 2 is C 3-7 alkyl.
15. 23 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 22 and a pharmaceutically acceptable vehicle therefor.
16. 24 . A method of treating a bacterial infection comprising administering to an individual in need thereof a pharmaceutical composition of claim 23 .
17. 25 . A compound having a structure of Formula (VII): wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, alkyl, —O-alkyl, NR A R B , —S-alkyl, —SO-alkyl, —SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, —O-alkyl, —COH, —C(O)—C 1-4 alkyl, —C(O)O—C 1-4 alkyl, NR C R D , —S-alkyl, —SO-alkyl and —SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; or a pharmaceutically acceptable salt, ester or ether thereof.
18. 26 . The compound of claim 25 , wherein R 3 is H, and R 4 is H or C 1-3 alkyl.
19. 27 . The compound of claim 26 , wherein R 2 is C 3-7 alkyl.
20. 28 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 27 and a pharmaceutically acceptable vehicle therefor.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of International Application No. PCT/US2022/050757, filed Nov. 22, 2022, which claims priority under 35 U.S.C. § 119(e) to U.S. App. No. 63/403,544, filed Sep. 2, 2022, and U.S. App. No. 63/283,431, filed Nov. 27, 2021. This application also claims priority under 35 U.S.C. § 119(e) to U.S. App. No. 63/524,381, filed Jun. 30, 2023, and U.S. App. No. 63/623,564, filed Jan. 22, 2024. Each of these applications is hereby incorporated by reference in its entirety. BACKGROUND The surfacing of bacterial resistance to a number of antimicrobial agents such as beta-lactam antibiotics, macrolides, quinolones, and vancomycin has become a pervasive health problem. A significant problem in clinical practice is the increased incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections. The mounting resistance of the important community acquired pathogen Streptococcus pneumoniae to penicillin and other antibacterial agents has become a global health problem. Multi drug-resistant strains of Mycobacterium tuberculosis have surfaced in several countries. The emergence and spread of resistant nosocomial and community-acquired pathogens has become a great menace to global public health. Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Anthrax most commonly occurs in wild and domestic lower vertebrates (e.g., cattle, sheep, goats, camels, antelopes, or other herbivores), but it can also occur in humans when they are exposed to infected animals or tissues from infected animals. In addition, Bacillus anthracis is one of the most important pathogens on the list of bioterrorism threats. The human LD50 for inhalational exposure is about 8,000 to 40,000 spores, or one deep breath at site of release. Anthrax infection can occur in at least three forms-namely, inhalational, cutaneous, and gastrointestinal. Inhalation anthrax occurs in several discrete steps. Endospores of Bacillus anthracis are taken up by macrophages at the site of initial infection and can be transported to regional lymph nodes. The spores germinate inside the phagolysosome to become vegetative bacteria which can escape from the phagolysosome and replicate within the cytoplasm. Vegetative cells are released into the extracellular milieu and enter the circulation where the vegetative cells grow extracellularly to levels as high as 108 bacteria per ml of blood. In this environment, the vegetative bacteria respond to physiological body temperature and CO2 levels to transcriptionally activate genes responsible for capsule formation and toxin synthesis. Finally, massive edema and organ failure are produced as a consequence of toxin formation. Experience with the 2001 bioterrorism incident found that once the disease reaches the phase where patients show evidence of significant toxin production, treatment with antibiotics can do little to prevent a fatal outcome. Similar results were reported in animal models. Accordingly, early diagnosis and intervention prior to toxin production is essential to patient survival. Bacillus anthracis can also produce cutaneous anthrax or gastrointestinal anthrax. Cutaneous or gastrointestinal anthrax may show local signs and symptoms. In some cases, cutaneous or gastrointestinal anthrax can disseminate to produce the sepsis syndrome that occurs following inhalation anthrax. Treatment of anthrax is dependent on administration of antibiotics early in the course of disease. Successful treatment requires that the bacterium be sensitive to available antibiotics and that antibiotics be administered before large amounts of toxin are released. A delay in antibiotic treatment may substantially lessen chances for survival. If a sufficient level of toxin production occurs, there is little in the way of specific therapy that is available for treatment. A further complication in the treatment of anthrax is the possibility that a biowarfare strain can be engineered to resist treatment by conventional antibiotics. For example, there is a report of a Bacillus anthracis strain that has been engineered to resist the tetracycline and penicillin classes of antibiotics. Similarly, the bacillus could be engineered to produce a toxin that would evade anthrax vaccines that target the anthrax toxin. Antibiotics have been increasingly investigated for their anti-inflammatory effects. In the setting of chronic rhinosinusitis, for example, macrolide and tetracycline antibiotics have been trialed for their anti-inflammatory properties. The anti-inflammatory mechanisms of macrolides include the downregulation of proinflammatory genes, improvement of mucociliary function, and decreased neutrophil accumulation. Observational studies provide support for a prolonged trial of macrolide therapy when conventional therapies fail, especially in patients with low serum IgE levels. Tetracyclines exert anti-inflammatory effects by decreasin